Journal
AGING CELL
Volume 14, Issue 1, Pages 60-66Publisher
WILEY
DOI: 10.1111/acel.12295
Keywords
aging phenotypes; association study; Forkhead box O3; oldest-old; SNPs
Categories
Funding
- Max-Planck Institute for Demographic Research (Rostock, Germany)
- European Union [259679]
- INTERREG 4 A programme Syddanmark-Schleswig-K.E.R.N. (by EU funds from the European Regional Development Fund)
- National Institute on Aging [P01 AG08761]
- Novo Nordisk Foundation
- Aase and Ejnar Danielsen Foundation
- Brodrene Hartmann Foundation
- King Christian the 10th Foundation
- Einer Willumsens Mindelegat Foundation
- VELUX Foundation
- Danish Council for Independent Research - Medical Sciences
- Novo Nordisk Fonden [NNF13OC0007043] Funding Source: researchfish
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FOXO3A variation has repeatedly been reported to associate with human longevity, yet only few studies have investigated whether FOXO3A variation also associates with aging-related traits. Here, we investigate the association of 15 FOXO3A tagging single nucleotide polymorphisms (SNPs) in 1088 oldest-old Danes (age 92-93) with 4 phenotypes known to predict their survival: cognitive function, hand grip strength, activity of daily living (ADL), and self-rated health. Based on previous studies in humans and foxo animal models, we also explore self-reported diabetes, cancer, cardiovascular disease, osteoporosis, and bone (femur/spine/hip/wrist) fracture. Gene-based testing revealed significant associations of FOXO3A variation with ADL (P=0.044) and bone fracture (P=0.006). The single-SNP statistics behind the gene-based analysis indicated increased ADL (decreased disability) and reduced bone fracture risk for carriers of the minor alleles of 8 and 10 SNPs, respectively. These positive directions of effects are in agreement with the positive effects on longevity previously reported for these SNPs. However, when correcting for the test of 9 phenotypes by Bonferroni correction, bone fracture showed borderline significance (P=0.054), while ADL did not (P=0.396). Although the single-SNP associations did not formally replicate in another study population of oldest-old Danes (n=1279, age 94-100), the estimates were of similar direction of effect as observed in the Discovery sample. A pooled analysis of both study populations displayed similar or decreased sized P-values for most associations, hereby supporting the initial findings. Nevertheless, confirmation in additional study populations is needed.
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